Variability in Inner Ear Morphology Among a Family With Pendred Syndrome Due to a SLC26A4 Gene Variant.

OBJECTIVES: Pendred syndrome, an autosomal recessive disorder, is often associated with pathogenic variants of the SLC26A4 gene that encodes the pendrin protein. Given its autosomal recessive inheritance, tracing the family history and screening siblings become crucial once a diagnosis of Pendred syndrome is confirmed. This case report aims to underscore the variability in inner ear morphology within a family diagnosed with Pendred syndrome, all carrying the same SLC26A4 gene mutation. METHODS: A chart review and a review of the literature. RESULTS: We present a family of 4, all of whom possess sensorineural hearing loss due to the same homozygous SLC26A4 variant c.919-2A>G. Intriguingly, clinical manifestations, especially inner ear deformities, displayed variability among family members. Notably, 1 family member exhibited a normal cochleovestibular structure morphology, which was rarely reported in the literature. CONCLUSIONS: This report highlights the significance of genetic testing and familial consultation when a proband exhibits typical Pendred syndrome symptoms. It also underscores that the inner ear morphology can exhibit variability among family members, even with the same homozygous SLC26A4 variant.

Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study.

PURPOSE: Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome. This study aimed to explore the prevalence of isolated IP-II, IP-II with EVA, and cases with a genetic or syndromic basis in our cohort. METHODS: From a large, multicentre database of dysplastic cochleae (446 patients, 892 temporal bones), those with imaging features of IP-II were examined in detail, including whether there was a genetic or syndromic association. RESULTS: A total of 78 patients with IP-II were identified. Among these, 55 patients had bilateral IP-II and EVA (only 12 with typical Mondini triad), 8 with bilateral IP-II and normal VA, 2 with bilateral IP-II and unilateral EVA, and 13 with unilateral IP-II (9 with unilateral EVA). Among the group with bilateral IP-II and bilateral EVA in whom genetic analysis was available, 14 out of 29 (48%) had SLC26A4 mutations and a diagnosis of Pendred syndrome, 1 had a FOXI1 mutation, and a few other genetic abnormalities; none had KCNJ10 pathogenic variants. CONCLUSION: Bilateral IP-II-bilateral EVA may be seen in the context of Pendred syndrome (SLC26A4 or FOXI1 mutations) but, in the majority of our cohort, no genetic abnormalities were found, suggesting the possibility of unknown genetic associations. IP-II in isolation (without EVA) is favored to be genetic when bilateral, although the cause is often unknown.

[Update on diagnostic procedures in third window syndromes. German version]. / Update zur Diagnostik der Drittfenstersyndrome.

BACKGROUND: The diagnosis of third window syndromes often poses a challenge in clinical practice. OBJECTIVE: This paper provides an up-to-date overview of diagnostic procedures in third window syndromes, with special emphasis on superior canal dehiscence syndrome (SCDS), large vestibular aqueduct syndrome (LVAS), and X-chromosomal malformation of the cochlea. MATERIALS AND METHODS: A literature search was performed in PubMed up to December 2023. Furthermore, a selection of the authors' own cases is presented. RESULTS: Audiovestibular tests for the diagnosis of third window syndromes are most often reported for patients with SCDS in the literature. In this context, cut-off values with different sensitivities and specificities have been defined for different outcome parameters of vestibular evoked myogenic potentials. Current developments include the application of electrocochleography, broadband tympanometry, video head impulse testing, and vibration-induced nystagmus. Genetic analyses are increasingly applied in LVAS. CONCLUSION: The diagnosis of third window syndromes is always based on the synthesis of patients' symptoms, clinical signs, audiovestibular test results, and imaging.

Enlarged vestibular aqueduct as a cause of postneonatal deafness.

INTRODUCTION: The enlarged vestibular aqueduct (EVA) is the most frequent malformation of the inner ear associated with sensorineural hearing loss (5-15%). It exists when the diameter in imaging tests is greater than 1.5 mm at its midpoint. The association between hearing loss and EVA has been described in a syndromic and non-syndromic manner. It can appear as a familial or isolated form and the audiological profile is highly variable. The gene responsible for sensorineural hearing loss associated with EVA is located in the same region described for Pendred syndrome, where the SCL26A4 gene is located. OBJECTIVE: To describe a series of children diagnosed with EVA in order to study their clinical and audiological characteristics, as well as the associated genetic and vestibular alterations. METHOD: Retrospective study of data collection of children diagnosed with EVA, from April 2014 to February 2023. RESULTS: Of the 17 cases, 12 were male and 5 were female. 5 of them were unilateral and 12 bilateral. In 5 cases, a cranial traumatism triggered the hearing loss. Genetic alterations were detected in 3 cases: 2 mutations in the SCL26A4 gene and 1 mutation in the MCT1 gene. 13 patients (76.5%) were rehabilitated with hearing aids and 9 of them required cochlear implantation. DISCUSSION: The clinical importance of AVD lies in the fact that it is a frequent finding in the context of postneonatal hearing loss. It is convenient to have a high suspicion to diagnose it with imaging tests, to monitor its evolution, and to rehabilitate early.

Study of the factors related to air-bone gap in enlarged vestibular aqueduct.

BACKGROUND: Over half of patients with enlarged vestibular aqueducts (EVA) will have an air-bonr gap (ABG), however, current research on audiology has focused on the influencing factors of air-conducted. OBJECTIVE: To retrospectively analyse the influencing factors and clinical manifestations of the bone-conduction threshold and ABG in patients with EVA. MATERIALS AND METHODS: We included 286 patients with EVA; among them, 126 had full SLC26A4 gene sequence results. We performed a descriptive analysis of the bone-conduction threshold and explored the effect of age. Finally, we analyzed the relationship of ABG and SLC26A4 genes with the degree of vestibular aqueduct (VA) enlargement. RESULTS: Among 555 ears, 312 (57.8%) ears had ABG; approximately 94% of the patients' bone-conduction hearing is almost completely lost at frequencies of 2 and 4 kHz. There was no linear correlation between age and bone-conduction threshold (p > 0.05). ABG did not significantly differ according to the degree of VA enlargement and number of SLC26A4 allele mutations (p > 0.05). CONCLUSIONS AND SIGNIFICANCE: Among patients with EVA, ABG is mainly produced at low frequencies and is not significantly correlated with age, size of the VA opening or SLC26A4 genes, which could be attributed to the biomechanical effects.

Study on characteristics of wideband acoustic immittance in patients with Inner Ear Malformations.

OBJECTIVE: To compare the differences in wideband absorbance and the resonance frequency (RF) between patients with inner ear malformations and normal control, and to explore the auditory diagnostic value of wideband acoustic immittance (WAI). METHODS: A total of 38 patients (59 ears) with enlarged vestibular aqueduct (EVA), 13 patients (14 ears) with incomplete partition type I (IP-I) and 13 patients (26 ears) with incomplete partition type II (IP-II) were included. 50 normal control (100 ears). All subjects underwent WAI tests to compare the absorbance configuration and resonance frequency. RESULTS: All the group showed lower absorbance at ambient pressure than at peak pressure in certain frequencies under 2000Hz. Under 1000Hz, the absorbance of EVA was higher than that of other groups. The average absorbance and highest absorbance of IP-I were the lowest(P＜0.05). However, IP-II and normal group had similarity on some characteristics. The three IEM groups mainly different at low and high frequencies, but not at medium frequencies. The highest absorbance of all the groups were appeared around 3000Hz. The RF of all the groups from low to high were EVA＜IP-II＜normal control＜IP-I, and the lowest was EVA(P＜0.05). CONCLUSION: Inner ear malformations can affect energy absorbance and RF. WAI is sensitive and non-invasive to provide useful information about inner ear status and facilitate detection of ear pathology.

The correlation between deafness progression and SLC26A4 mutations in enlarged vestibular aqueduct patients.

BACKGROUND: The relationship between the hearing phenotype and the SLC26A4 mutation in enlarged vestibular aqueduct cases has not been fully elucidated. OBJECTIVES: To detect SLC26A4 mutation in a group of cases with enlarged vestibular aqueduct who received cochlear implantation and to analyze the correlation between the SLC26A4 genotype and the progression of deafness. MATERIALS AND METHODS: Twenty-nine enlarged vestibular aqueduct patients were selected. Using the Sanger sequence to analyze SLC26A4 gene mutations. The 29 cases were divided into group A (carrying the c.919-2A > G mutation) and group B (not carrying the c.919-2A > G mutation). The difference in the duration of deafness was analyzed between the two groups. RESULTS: The detection rate of the c.1174A > T mutation in the postlingual deafness group was 37.5%, higher than that in the prelingual deafness group (0%). The difference in the duration of deafness between groups A and B was not statistically significant by the Mann-Whitney U test (p > 0.05). CONCLUSIONS: The correlation between the SLC26A4 genotype and the duration of deafness in cases with enlarged vestibular aqueduct is not yet clear. However, the c.1174A > T mutation may be linked to delayed hearing loss and the progression of deafness may be relatively slow in some cases of c.919-2A > G mutation.

Non-Syndromic Sensorineural Hearing Loss in Children.

Pediatric hearing loss is common with significant consequences in terms of language, communication, social and emotional development, and academic advancement. Radiological imaging provides useful information regarding hearing loss etiology, prognosis, therapeutic options, and potential surgical pitfalls. This review provides an overview of temporal bone imaging protocols, an outline of the classification of inner ear anomalies associated with sensorineural hearing loss and illustrates some of the more frequently encountered and/or important causes of non-syndromic hearing loss.

Non-syndromic enlarged vestibular aqueduct caused by novel compound mutations of the SLC26A4 gene: a case report and literature review.

Enlarged vestibular aqueduct is an autosomal genetic disease mainly caused by mutations in the SLC26A4 gene and includes non-syndromic and syndromic types. This study aimed to identify genetic defects in a Chinese patient with non-syndromic enlarged vestibular aqueduct (NSEVA) and to investigate the impact of variants on the severity of non-syndromic enlarged vestibular aqueduct. A male patient with NSEVA, aged approximately 6 years, was recruited for this study. The clinical characteristics and results of auxiliary examinations, including laboratory and imaging examinations, were collected, and 127 common hereditary deafness genes were detected by chip capture high-throughput sequencing. Protein structure predictions, the potential impact of mutations, and multiple sequence alignments were analyzed in silico. Compound heterozygote mutations c.1523_1528delinsAC (p.Thr508Asnfs*3) and c.422T>C (p.Phe141Ser) in the SLC26A4 gene were identified. The novel frameshift mutation c.1523_1528delinsAC produces a severely truncated pendrin protein, and c.422T>C has been suggested to be a disease-causing mutation. Therefore, this study demonstrates that the novel mutation c.1523_1528delinsAC in compound heterozygosity with c.422T>C in the SLC26A4 gene is likely to be the cause of NSEVA. Cochlear implants are the preferred treatment modality for patients with NSEVA and severe-to-profound sensorineural hearing loss Genetic counseling and prenatal diagnosis are essential for early diagnosis. These findings expand the mutational spectrum of SLC26A4 and improve our understanding of the molecular mechanisms underlying NSEVA.

Correlation Between Air-Bone Gap and Vestibular Aqueduct Size in Enlarged Vestibular Aqueduct Syndrome: A Systematic Review.

The purpose of this review was to evaluate the air-bone gap with vestibular aqueduct size in enlarged vestibular aqueduct syndrome. According to the PRISMA guidelines we conducted a systematic review of the literature. Published international articles in English from 2000 to 2022 were screened, checking for studies that evaluated the air-bone gap of patients affected by enlarged vestibular aqueduct syndrome and the size of vestibular aqueduct. Data related to the hearing assessment and imaging investigation of enrolled participants were extracted. The chosen primary outcome measure was the correlation between air-bone-gap and vestibular aqueduct size. The database search allowed us to screen 485 articles and to select 5 articles discussing this topic for a total of 349 patients. Two studies showed a positive correlation between air-bone gap and vestibular aqueduct size, one only a trend and two no correlation. To date, it is not possible to draw conclusions whether or not there is a positive correlation between air-bone gap and vestibular aqueduct size in enlarged vestibular aqueduct syndrome. Higher quality studies would be conducted with standardized outcome measures to clarify the specific research question.

A Large Vestibular Aqueduct With Conductive Hearing Loss as the Only Manifestation.

Conductive hearing loss is a common clinical condition caused by disorders of the middle and external ear. Here, we report a case of conductive hearing loss with complete tympanic membranes. Clinical examinations revealed no external and middle ear lesions, but high-resolution temporal bone computed tomography revealed enlarged vestibular aqueducts. Detailed audiological tests and follow-up results indicate that the exclusive air-bone gap is the outcome of inner ear malformation but not middle ear lesions, preventing the need for tympanic assessment.

Evidence of vestibular dysfunction in children with enlarged vestibular aqueduct.

OBJECTIVE: To investigate the occurrence and characteristics of balance and vestibular deficits in pediatric patients with enlarged vestibular aqueduct (EVA). MATERIALS AND METHODS: Retrospective review of 53 children with EVA who underwent a comprehensive vestibular evaluation in our pediatric balance and vestibular program. Laboratory testing included videonystagmography (VNG), rotary chair, video head impulse testing (vHIT), vestibular evoked myogenic potential (VEMP), subjective visual vertical (SVV) and Sensory Organization Test (SOT) in posturography. RESULTS: The mean age of these children, 31 girls and 22 boys, was 7.1 years (SD = 4.8). Among these 53 children, 16 had unilateral EVA (7 on the left side and 9 on the right side) and 37 had bilateral EVA, in which genetic testing confirmed 5 cases of Pendred syndrome. Abnormal testing results were found in 58% (11/19) on SOT, 67% (32/48) on rotary chair, 55% (48/88 of ears) on VEMP, 30% (8/27) on vHIT, 39% (7/18) on SVV, and 8% (4/53) on VNG. CONCLUSIONS: Vestibular dysfunction may be a common finding in children with EVA. Clinicians who provide medical care for children with EVA need to be familiar with signs of potential balance and vestibular impairments. Although performing vestibular evaluation on young children with EVA can be difficult, objective testing is important in order to identify any potential vestibular deficit in these pediatric patients so that proper vestibular rehabilitation and balance retraining can be provided.

A Peculiar Case of Ossicular Chain Fixation and Enlarged Vestibular Aqueduct.

We present the case of a patient treated as affected by conductive hearing loss due to recurrent otitis, then as a juvenile otosclerosis, who was finally diagnosed as affected by bilateral ossicular chain fixation and enlarged vestibular aqueduct by means of cone-beam CT.

The Genetic Background of Hearing Loss in Patients with EVA and Cochlear Malformation.

The most frequently observed congenital inner ear malformation is enlarged vestibular aqueduct (EVA). It is often accompanied with incomplete partition type 2 (IP2) of the cochlea and a dilated vestibule, which together constitute Mondini malformation. Pathogenic SLC26A4 variants are considered the major cause of inner ear malformation but the genetics still needs clarification. The aim of this study was to identify the cause of EVA in patients with hearing loss (HL). Genomic DNA was isolated from HL patients with radiologically confirmed bilateral EVA (n = 23) and analyzed by next generation sequencing using a custom HL gene panel encompassing 237 HL-related genes or a clinical exome. The presence and segregation of selected variants and the CEVA haplotype (in the 5' region of SLC26A4) was verified by Sanger sequencing. Minigene assay was used to evaluate the impact of novel synonymous variant on splicing. Genetic testing identified the cause of EVA in 17/23 individuals (74%). Two pathogenic variants in the SLC26A4 gene were identified as the cause of EVA in 8 of them (35%), and a CEVA haplotype was regarded as the cause of EVA in 6 of 7 patients (86%) who carried only one SLC26A4 genetic variant. In two individuals with a phenotype matching branchio-oto-renal (BOR) spectrum disorder, cochlear hypoplasia resulted from EYA1 pathogenic variants. In one patient, a novel variant in CHD7 was detected. Our study shows that SLC26A4, together with the CEVA haplotype, accounts for more than half of EVA cases. Syndromic forms of HL should also be considered in patients with EVA. We conclude that to better understand inner ear development and the pathogenesis of its malformations, there is a need to look for pathogenic variants in noncoding regions of known HL genes or to link them with novel candidate HL genes.

Newborn Hearing Screening Results in Patients with Enlarged Vestibular Aqueduct.

OBJECTIVES: Enlarged vestibular aqueduct (EVA) is the most common anatomic abnormality contributing to permanent hearing loss (HL) in children. Although the association between EVA and HL is well-documented, the pass rate for the newborn hearing screening (NBHS) for patients with EVA-related HL is not. Our objective was to investigate the association between NBHS results and audiologic and clinical outcomes in a large cohort of pediatric patients with EVA. METHODS: This was a retrospective chart review of patients seen in the Boston Children's Hospital (BCH) Department of Otolaryngology and Communication Enhancement with confirmed HL, known NBHS results, and confirmed EVA. Demographic, clinical, audiologic, and imaging data were collected from the medical record. Frequency-specific data points from pure-tone audiograms and/or automated auditory brainstem response tests were recorded, and four-frequency pure tone average was calculated using air conduction thresholds at 500, 1000, 2000, and 4000 Hz. RESULTS: Of the 183 patients included in the study, 84 (45.9%) passed their NBHS, whereas 99 (54.1%) did not pass. Compared with patients who did not pass, patients who passed were more likely to have unilateral EVA and unilateral HL, whereas they were less likely to undergo cochlear implantation and to have causative SLC26A4 variants. CONCLUSIONS: EVA-associated HL may be identified at birth or during childhood, with nearly half the patients in this cohort passing their NBHS. Our results provide prognostic information for patients with EVA who pass their NBHS and highlight the importance of regular hearing monitoring for children not initially suspected of having HL. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2786-2791, 2023.

Cochlear Implantation: The Volumetric Measurement of Vestibular Aqueduct and Gusher Prediction.

This study aimed to validate the role of 3D segmentation in measuring the volume of the vestibular aqueduct (VAD), and the inner ear, and to study the correlation between VAD volume and VAD linear measurements at the midpoint and operculum. The correlation with other cochlear metrics was also studied. We retrospectively recruited 21 children (42 ears) diagnosed with Mondini dysplasia (MD) plus enlarged vestibular aqueduct (EVA) from 2009 to 2021 and who underwent cochlear implantation (CI). Patients' sociodemographic data were collected, and linear cochlear metrics were measured using Otoplan. Vestibular aqueduct width and vestibular aqueduct and inner ear volumes were measured by two independent neuro-otologists using 3D segmentation software (version 4.11.20210226) and high-resolution CT. We also conducted a regression analysis to determine the association between these variables and CT VAD and inner ear volumes. Among the 33 cochlear implanted ears, 13 ears had a gusher (39.4%). Regarding CT inner ear volume, we found that gender, age, A-value, and VAD at the operculum were statistically significant (p-Value = 0.003, <0.001, 0.031, and 0.027, respectively) by regression analysis. Moreover, we found that Age, H value, VAD at the midpoint, and VAD at the operculum were significant predictors of CT VAD volume (p-Value < 0.04). Finally, gender (OR: 0.092; 95%CI: 0.009-0.982; p-Value = 0.048) and VAD at the midpoint (OR: 0.106; 95%CI: 0.015-0.735; p-Value = 0.023) were significant predictors of gusher risk. Patients' gusher risk was significantly differentiated by gender and VAD width at the midpoint.

Potencial miogênico evocado vestibular cervical em crianças e adolescentes com aqueduto vestibular alargado: revisão sistemática / Cervical vestibular evoked myogenic potential in children and adolescents with enlarged vestibular aqueduct: systematic review

RESUMO Objetivo Reunir os parâmetros encontrados no potencial miogênico evocado vestibular cervical (cVEMP) em crianças e adolescentes com síndrome do aqueduto vestibular alargado (SAVA) e identificar as possíveis alterações, quando comparados aos valores encontrados em normo-ouvintes da mesma faixa etária. Estratégia de pesquisa Revisão sistemática cadastrada na base PROSPERO, elaborada por meio de busca nos bancos de dados virtuais, a partir dos unitermos selecionados. Critérios de seleção Incluídos artigos científicos disponíveis na íntegra que relataram a avaliação com o uso do cVEMP na faixa etária entre 0 e 18 anos, com diagnóstico de SAVA, sem restrição de idioma e ano de publicação; excluídos estudos em paciente com algum distúrbio, outras patologias otoneurológicas e população fora da faixa etária estimada. Resultados Foram identificados 984 registros, a partir da pesquisa nas bases de dados consultadas e selecionados 5 artigos. Em um total de 133 pacientes que realizaram o cVEMP, foi observada presença de resposta na maioria dos casos, sem diferença significativa nas latências, mas com aumento na amplitude e diminuição nos limiares do cVEMP. Conclusão O teste cVEMP é recomendado na avaliação de crianças e adolescentes com SAVA e as características de aumento na amplitude e diminuição nos limiares podem ser utilizadas como parâmetros clínicos na identificação da referida síndrome, juntamente com a história clínica do paciente e os exames de imagem. No entanto, é imprescindível a realização de mais estudos com o exame cVEMP, ainda, em crianças e adolescentes com SAVA, para a melhor padronização dos valores encontrados, a fim de efetivar o diagnóstico correto.

ABSTRACT Purpose To gather the parameters found in the cervical vestibular evoked myogenic potential (cVEMP) in children and adolescents with enlarged vestibular aqueduct syndrome (SAVA) and identify the possible changes, when compared to the values found in normal hearing people of the same age group. Research strategy Systematic review registered in the PROSPERO database, prepared through a search in virtual databases, based on the selected keywords. Selection criteria Included scientific articles available in full that reported the evaluation using cVEMP in the 0 and 18 years old group , with a diagnosis of SAVA, without restrictions of language and year of publication; Studies on patients with any disorder other than otoneurological ones and populations outside the proposed age range were excluded. Results 984 records were identified from the search in the databases consulted and 5 articles were selected. In a total of 133 patients who underwent cVEMP, the presence of a response was observed in most cases, with no significant difference in latencies, but with an increase in amplitude and a decrease in cVEMP thresholds. Conclusion The cVEMP test is recommended in the evaluation of children and adolescents with SAVA and the characteristics of increase in amplitude and decrease in thresholds can be used as clinical parameters in the identification of this syndrome, together with the patient's clinical history and imaging exams. However, it is essential to carry out more studies with the cVEMP test, also in children and adolescents with SAVA, to better standardize the values found, in order to make the correct diagnosis.

Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies

Pathogenic variants in the SLC26A4, FOXI1, and KCNJ10 genes are associated with hearing loss (HL) and specific inner ear abnormalities (DFNB4). In the present study, phenotype analyses, including clinical data collection, computed tomography (CT), and audiometric examination, were performed on deaf individuals from the Sakha Republic of Russia (Eastern Siberia). In cases with cochleovestibular malformations, molecular genetic analysis of the coding regions of the SLC26A4, FOXI1, and KCNJ10 genes associated with DFNB4 was completed. In six of the 165 patients (3.6%), CT scans revealed an incomplete partition of the cochlea (IP-1 and IP-2), in isolation or combined with an enlarged vestibular aqueduct (EVA) anomaly. Sequencing of the SLC26A4, FOXI1, and KCNJ10 genes was performed in these six patients. In the SLC26A4 gene, we identified four variants, namely c.85G>C p.(Glu29Gln), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln), and c.2089+1G>A (IVS18+1G>A), which are known as pathogenic, as well as c.441G>A p.(Met147Ile), reported previously as a variant with uncertain significance. Using the AlphaFold algorithm, we found in silico evidence of the pathogenicity of this variant. We did not find any causative variants in the FOXI1 and KCNJ10 genes, nor did we find any evidence of digenic inheritance associated with double heterozygosity for these genes with monoallelic SLC26A4 variants. The contribution of biallelic SLC26A4 variants in patients with IP-1, IP-2, IP-2+EVA, and isolated EVA was 66.7% (DFNB4 in three patients, Pendred syndrome in one patient). Seventy-five percent of SLC26A4-biallelic patients had severe or profound HL. The morphology of the inner ear anomalies demonstrated that, among SLC26A4-biallelic patients, all types of incomplete partition of the cochlea are possible, from IP-1 and IP-2, to a normal cochlea. However, the dominant type of anomaly was IP-2+EVA (50.0%). This finding is very important for cochlear implantation, since the IP-2 anomaly does not have an increased risk of "gushers" and recurrent meningitis.

SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management.

SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.

[Relationship between imaging features and intraoperative perilymph gusher in patients with Mondini inner ear malformation].

Objective:To investigate the relationship between imaging characteristics and intraoperative perilymph gusher in patients with Mondini inner ear malformation in cochlear implantation, in order to provide basis and clinical guidance for predicting of intraoperative perilymph gusher before cochlear implantation. Methods:According to Sennaroglu's classification method, children with severe sensorineural hearing loss screened from January 2020 to December 2021 were divided into Mondini group, simple enlarged vestibular aqueduct group and normal inner ear group according to inclusion criteria strictly. The images of temporal bone HRCT and inner ear MRI were post-processed, some relative indicators were measured, including cochlear height and width of vestibular aqueduct, etc., and the gusher situation during cochlear implantation was recorded. The mean value of each indicator among the three groups were compared respectively, and the differences of each indicator between the gusher group and the non-gusher group were analyzed. Results:There were statistically significant differences in cochlear height, length of cochlear bottom turn, width of cochlear aperture, vestibular length and vestibular width among the Mondini group（24 cases）, simple EVA group（15 cases） and normal inner ear group（28 cases）. The incidence of gusher of Mondini group in cochlear implantation was 30.77%（8/26）. The outer diameter of the VA（[3.10±0.74]mm） and the middle width of the VA（[1.90±0.68] mm） in the gusher group were wider than those in the non-gusher group, and the difference was statistically significant. The incidence of intraoperative gusher in patients with EVA was 20.00%（3/15）, and there was statistically significant difference in the length of endolymph sac between gusher group and non-gusher group（P<0.05）. Conclusion:The causes of intraoperative perilymph gusher in patients with Mondini inner ear malformation are complex. The enlarged vestibular aqueduct may be one of the anatomical basis. Whether it can be used to guide the preoperative assessment of the risk of intraoperative perilymph gusher need to be further confirmed by a large sample of clinical research from multiple centers in the future.